ACUTE AND CHRONIC

INFLAMMATION
 INFLAMMATION
A PROTECTIVE RESPONSE INVOLVING HOST CELLS, BLOOD
VESSELS AND PROTEINS.
GOALS ARE:
• ELIMINATE THE INITIAL CAUSE OF CELL INJURY
• REMOVE NECROTIC CELLS AND TISSUE
• INITIATE THE PROCESS OF REPAIR

ALSO A POTENTIALLY HARMFUL PROCESS:

• COMPONENTS OF INFLAMMATION THAT ARE CAPABLE OF
DESTROYING MICROBES CAN ALSO INJURE BYSTANDER
NORMAL TISSUE.
 INFLAMMATION
• COMPONENTS OF THE INFLAMMATORY PROCESS INCLUDE WHITE
BLOOD CELLS AND PLASMA PROTEINS:

 NORMALLY PRESENT IN THE BLOOD

 THE INFLAMMATORY REACTION’S GOAL IS TO BRING THESE TO THE

SITE OF INFECTION AND/OR TISSUE DAMAGE

• INFLAMMATION IS INDUCED BY CHEMICAL MEDIATORS PRODUCED

BY :

 DAMAGED HOST CELLS

 CYTOKINES AND OTHER MEDIATORS

• INFLAMMATION IS NORMALLY CONTROLLED AND SELF-LIMITED .

 EXCESS
INFLAMMATO
RY • INAPPROPRIATE
REACTIONS INFLAMMATORY
RESPONSE WHEN THERE
ARE NO FOREIGN
SUBSTANCES TO FIGHT OFF
LEADS TO AUTOIMMUNITY.

• INFLAMMATORY PROCESS
MUST BE TIGHTLY
REGULATED BY THE
IMMUNE SYSTEM TO AVOID
EXCESSIVE TISSUE
DAMAGE AND SPILLOVER
 CARDINAL SIGNS OF
INFLAMMATION
• HEAT (CALOR)
• REDNESS (RUBOR)
• SWELLING (TUMOR)
• PAIN (DOLOR)
• LOSS OF FUNCTION
COMPONENTS OF ACUTE AND
CHRONIC INFLAMMATION
ACUTE V.S CHRONIC
INFLAMMATION
 ACUTE INFLAMMATION
STIMULI FOR ACUTE INFLAMMATION :

 INFECTIONS (BACTERIAL, VIRAL, FUNGAL, PARASITIC) & MICROBIAL

TOXINS

 TISSUE NECROSIS: ISCHEMIA, TRAUMA, PHYSICAL OR CHEMICAL

INJURY (E.G., THERMAL INJURY; IRRADIATION; SOME
ENVIRONMENTAL CHEMICALS)

 FOREIGN BODIES (SPLINTERS, DIRT, SUTURES)

 IMMUNE REACTIONS (ALSO CALLED HYPERSENSITIVITY REACTIONS)

 ACUTE
INFLAMMATI MAIN COMPONENTS:
ON
VASCULAR CHANGES:
o VASODILATION.
o VASCULAR PERMEABILITY.
o INCREASED ADHESION OF WHITE
BLOOD CELLS.

 CELLULAR EVENTS
o CELLULAR RECRUITMENT AND
ACTIVATION OF NEUTROPHILS
(POLYMORPHONUCLEAR
LEUKOCYTES).
 ACUTE INFLAMMATION
1. VASODILATION:
ALTERATIONS IN VASCULAR CALIBER (DIAMETER) :
- CAUSES DECREASE IN BLOOD PRESSURE

2. VASCULAR LEAKAGE AND EDEMA:

- THE ACCUMULATION OF FLUID AND PROTEINS OF PLASMA IN
THE EXTRAVASCULAR TISSUES (INTERSTITIUM)

3. LEUKOCYTE EMIGRATION TO EXTRAVASCULAR TISSUES:

A. MARGINATION AND ROLLING
B. ACTIVATION AND ADHESION
C. TRANSMIGRATION
 VASODILATION .1
VASODILATION IS ONE OF THE EARLIEST
MANIFESTATIONS OF ACUTE INFLAMMATION;
SOMETIMES IT FOLLOWS A TRANSIENT
CONSTRICTION OF ARTERIOLES, LASTING A
FEW SECONDS.
VASODILATION FIRST INVOLVES THE
ARTERIOLES AND THEN LEADS TO OPENING OF
NEW CAPILLARY BEDS IN THE AREA. THE
RESULT IS INCREASED BLOOD FLOW, WHICH IS
THE CAUSE OF HEAT AND REDNESS
(ERYTHEMA) AT THE SITE OF INFLAMMATION.
VASODILATION IS INDUCED BY THE ACTION OF
 VASODILATION

• VASODILATION IS QUICKLY FOLLOWED BY INCREASED

PERMEABILITY OF THE MICROVASCULATURE, WITH THE
OUTPOURING OF PROTEIN-RICH FLUID INTO THE EXTRAVASCULAR
TISSUES

• THE LOSS OF FLUID AND INCREASED VESSEL DIAMETER LEAD TO

SLOWER BLOOD FLOW, CONCENTRATION OF RED CELLS IN SMALL
VESSELS, AND INCREASED VISCOSITY OF THE BLOOD.

• THESE CHANGES RESULT IN DILATION OF SMALL VESSELS THAT ARE

PACKED WITH SLOWLY MOVING RED CELLS, A CONDITION TERMED
STASIS, WHICH IS SEEN AS VASCULAR CONGESTION (PRODUCING
LOCALIZED REDNESS) UPON EXAMINATION OF THE INVOLVED TISSUE.
 VASODILATION
• AS STASIS DEVELOPS, BLOOD LEUKOCYTES, PRINCIPALLY
NEUTROPHILS, ACCUMULATE ALONG THE VASCULAR
ENDOTHELIUM.
• AT THE SAME TIME ENDOTHELIAL CELLS ARE ACTIVATED BY
MEDIATORS PRODUCED AT SITES OF INFECTION AND TISSUE
DAMAGE, AND EXPRESS INCREASED LEVELS OF ADHESION
MOLECULES.
• LEUKOCYTES THEN ADHERE TO THE ENDOTHELIUM, AND SOON
AFTERWARD THEY MIGRATE THROUGH THE VASCULAR WALL INTO
THE INTERSTITIAL TISSUE.
 VASCULAR LEAKAGE AND .2
EDEMA
• OUTPOURING OF PROTEIN-RICH FLUID (EXUDATE)
INTO THE EXTRACELLULAR TISSUES LEADS TO:
REDUCTION OF INTRAVASCULAR OSMOTIC
PRESSURE
INCREASE IN EXTRAVASCULAR/INTERSTITIAL
OSMOTIC PRESSURE

• INCREASE OF INTERSTITIAL OSMOTIC PRESSURE

LEADS TO EDEMA (WATER AND IONS)
MECHANISMS OF INCREASED VASCULAR PERMEABILITY

A. CONTRACTION OF ENDOTHELIAL CELLS RESULTING IN INCREASED

INTERENDOTHELIAL SPACES:
 HISTAMINES, BRADYKININS, LEUKOTRIENES, THE NEUROPEPTIDE
SUBSTANCE P
B. ENDOTHELIAL INJURY RESULTING IN ENDOTHELIAL CELL NECROSIS AND
DETACHMENT.
 ENCOUNTERED IN SEVERE INJURIES, FOR EXAMPLE, IN BURNS, OR BY THE
ACTIONS OF MICROBES THAT TARGET ENDOTHELIAL CELLS.
 NEUTROPHILS THAT ADHERE TO THE ENDOTHELIUM DURING
INFLAMMATION MAY ALSO INJURE THE ENDOTHELIAL CELLS AND THUS
AMPLIFY THE REACTION.
 IN MOST INSTANCES LEAKAGE STARTS IMMEDIATELY AFTER INJURY AND
IS SUSTAINED FOR SEVERAL HOURS UNTIL THE DAMAGED VESSELS ARE
THROMBOSED OR REPAIRED.
C. TRANSCYTOSIS: INCREASED TRANSPORT OF FLUIDS AND PROTEINS
THROUGH THE ENDOTHELIAL CELL. THIS PROCESS MAY INVOLVE
CHANNELS CONSISTING OF INTERCONNECTED, UNCOATED VESICLES AND
 MECHANISMS OF INCREASED
VASCULAR PERMEABILITY
• ALTHOUGH THESE MECHANISMS OF INCREASED
VASCULAR PERMEABILITY ARE DESCRIBED
SEPARATELY, ALL PROBABLY CONTRIBUTE IN
VARYING DEGREES IN RESPONSES TO MOST
STIMULI.

• THE VASCULAR LEAKAGE INDUCED BY ALL THESE

MECHANISMS CAN CAUSE LIFE-THREATENING
LOSS OF FLUID IN SEVERELY BURNED PATIENTS.
 REACTIONS OF BLOOD VESSELS
IN ACUTE INFLAMMATION

• IN INFLAMMATION, BLOOD VESSELS UNDERGO A

SERIES OF CHANGES THAT ARE DESIGNED TO
MAXIMIZE THE MOVEMENT OF PLASMA PROTEINS
AND CIRCULATING CELLS OUT OF THE
CIRCULATION AND INTO THE SITE OF INFECTION
OR INJURY.

• THE ESCAPE OF FLUID, PROTEINS, AND BLOOD

CELLS FROM THE VASCULAR SYSTEM INTO THE
INTERSTITIAL TISSUE OR BODY CAVITIES IS
KNOWN AS EXUDATION.
 EXUDATE

Is an extravascular fluid that has a high protein concentration,

contains cellular debris, and has a high specific gravity.
Its presence implies an increase in the normal permeability of
small blood vessels in an area of injury and, therefore, an
inflammatory reaction .
 EXUDATE V.S TRANSUDATE
 TRANSUDATE : A FLUID WITH LOW PROTEIN CONTENT (MOST OF
WHICH IS ALBUMIN), LITTLE OR NO CELLULAR MATERIAL, AND LOW
SPECIFIC GRAVITY.
 AN ULTRAFILTRATE OF BLOOD PLASMA THAT RESULTS FROM
OSMOTIC OR HYDROSTATIC IMBALANCE ACROSS THE VESSEL WALL
WITHOUT AN INCREASE IN VASCULAR PERMEABILITY .
 A. THE MEAN COLLOID OSMOTIC
FORMATION OF
PRESSURE OF TISSUES IS
TRANSUDATES
APPROXIMATELY 25 MM HG
WHICH ISAND
EQUAL TOEXUDATES
,)GREEN ARROWS(
THE MEAN CAPILLARY PRESSURE. THE NET
FLOW OF FLUID ACROSS THE VASCULAR BED
.IS ALMOST NIL

B. A TRANSUDATE IS FORMED WHEN

FLUID LEAKS OUT BECAUSE OF
INCREASED HYDROSTATIC
PRESSURE OR DECREASED OSMOTIC
.PRESSURE

C. AN EXUDATE IS FORMED IN
INFLAMMATION, BECAUSE
VASCULAR PERMEABILITY
INCREASES AS A RESULT OF
INCREASED INTERENDOTHELIAL
 DEFINITIONS
• EDEMA DENOTES AN EXCESS OF FLUID IN
THE INTERSTITIAL TISSUE OR SEROUS
CAVITIES; IT CAN BE EITHER AN EXUDATE
OR A TRANSUDATE.

• PUS : IS A PURULENT EXUDATE, RICH IN

LEUKOCYTES (MOSTLY NEUTROPHILS),
THE DEBRIS OF DEAD CELLS AND, IN MANY
CASES, MICROBES.
 RESPONSES OF LYMPHATIC
VESSELS
 THE SYSTEM OF LYMPHATICS AND LYMPH NODES FILTERS AND
POLICES THE EXTRAVASCULAR FLUIDS.

 LYMPHATICS NORMALLY DRAIN THE SMALL AMOUNT OF

EXTRAVASCULAR FLUID THAT HAS SEEPED OUT OF
CAPILLARIES

 IN INFLAMMATION LYMPH FLOW IS INCREASED AND HELPS

DRAIN EDEMA FLUID THAT ACCUMULATES , DUE TO INCREASED
VASCULAR PERMEABILITY
 FLUID, LEUKOCYTES, CELL DEBRIS AND MICROBES, MAY FIND
THEIR WAY INTO LYMPH
 LYMPHATIC VESSELS, LIKE BLOOD VESSELS, PROLIFERATE
• THE LYMPHATICS MAY BECOME
SECONDARILY INFLAMED
(LYMPHANGITIS), AS MAY THE DRAINING
LYMPH NODES (LYMPHADENITIS).
• INFLAMMATORY/REACTIVE
LYMPHADENITIS: INFLAMED LYMPH
NODES ARE ENLARGED BECAUSE OF
HYPERPLASIA OF THE LYMPHOID
FOLLICLES AND INCREASED NUMBERS
OF LYMPHOCYTES AND
MACROPHAGES.
• LYMPHANGITIS: THE PRESENCE OF
RED STREAKS NEAR A SKIN WOUND IS
A TELLTALE SIGN OF AN INFECTION IN
THE WOUND. THIS STREAKING
FOLLOWS THE COURSE OF THE
LYMPHATIC CHANNELS.
 LEUKOCYTES EMIGRATION TO
EXTRAVASCULAR TISSUES
• THE JOURNEY OF LEUKOCYTES FROM THE VESSEL LUMEN TO THE
INTERSTITIAL TISSUE, CALLED EXTRAVASATION, CAN BE DIVIDED INTO THE
FOLLOWING STEPS:
1. IN THE LUMEN: MARGINATION, ROLLING, AND ADHESION TO ENDOTHELIUM
2. MIGRATION ACROSS THE ENDOTHELIUM AND VESSEL WALL
3. MIGRATION IN THE TISSUES TOWARD A CHEMOTACTIC STIMULUS
 A. MARGINATION, ROLLING, AND ADHESION TO
ENDOTHELIUM

• IN NORMALLY FLOWING BLOOD IN VENULES, RED CELLS ARE

CONFINED TO A CENTRAL AXIAL COLUMN, DISPLACING THE
LEUKOCYTES TOWARD THE WALL OF THE VESSEL.

• IN INFLAMMATION :BLOOD FLOW SLOWS EARLY (STASIS), AND

MORE WHITE CELLS ASSUME A PERIPHERAL POSITION ALONG THE
ENDOTHELIAL SURFACE. THIS PROCESS OF LEUKOCYTE
REDISTRIBUTION IS CALLED MARGINATION.

• INDIVIDUAL AND THEN ROWS OF LEUKOCYTES ADHERE

TRANSIENTLY TO THE ENDOTHELIUM, DETACH AND BIND AGAIN,
THUS ROLLING ON THE VESSEL WALL. THE CELLS FINALLY COME TO
REST AT SOME POINT WHERE THEY ADHERE FIRMLY (RESEMBLING
PEBBLES OVER WHICH A STREAM RUNS WITHOUT DISTURBING
THEM).
 INITIAL ROLLING INTERACTIONS ARE MEDIATED BY A FAMILY OF
PROTEINS CALLED SELECTINS.
THERE ARE THREE TYPES OF SELECTINS
i. E-SELECTIN: ENDOTHELIUM
ii. P-SELECTIN : PLATELETES, ENDOTHELIUM
iii. L-SELECTINS: LEUKOCYTES

 ON THE LEUKOCYTES THE LIGANDS FOR SELECTINS ARE SIALYLATED

OLIGOSACCHARIDES BOUND TO MUCIN-LIKE GLYCOPROTEIN
BACKBONES.
 THE EXPRESSION OF SELECTINS AND THEIR LIGANDS IS REGULATED
BY CYTOKINES PRODUCED IN RESPONSE TO INFECTION AND INJURY.
• LEUKOCYTES EXPRESS L-SELECTIN AT THE TIPS OF THEIR
MICROVILLI AND ALSO EXPRESS LIGANDS FOR E- AND P-
SELECTINS, ALL OF WHICH BIND TO THE COMPLEMENTARY
MOLECULES ON THE ENDOTHELIAL CELLS.
• THESE ARE LOW-AFFINITY INTERACTIONS WITH A FAST OFF-RATE,
AND THEY ARE EASILY DISRUPTED BY THE FLOWING BLOOD. AS A
RESULT, THE BOUND LEUKOCYTES BIND, DETACH, AND BIND
AGAIN, AND BEGIN TO ROLL ALONG THE ENDOTHELIAL SURFACE
 REGULATION OF EXPRESSION OF ENDOTHELIAL AND LEUKOCYTE ADHESION
MOLECULES

• TISSUE MACROPHAGES, MAST CELLS, AND ENDOTHELIAL CELLS

THAT ENCOUNTER MICROBES AND DEAD TISSUES RESPOND BY
SECRETING SEVERAL CYTOKINES, INCLUDING TUMOR NECROSIS
FACTOR (TNF), INTERLEUKIN-1 (IL-1), AND CHEMOKINES
(CHEMOATTRACTANT CYTOKINES).
• TNF AND IL-1 ACT ON THE ENDOTHELIAL CELLS OF POST-CAPILLARY
VENULES ADJACENT TO THE INFECTION AND INDUCE THE
COORDINATE EXPRESSION OF NUMEROUS ADHESION MOLECULES .
• WITHIN 1 TO 2 HOURS THE ENDOTHELIAL CELLS BEGIN TO EXPRESS
E-SELECTIN AND THE LIGANDS FOR L-SELECTIN.
• OTHER MEDIATORS SUCH AS HISTAMINE, THROMBIN, AND
PLATELET-ACTIVATING FACTOR (PAF),STIMULATE THE
REDISTRIBUTION OF P-SELECTIN FROM ITS NORMAL
INTRACELLULAR STORES IN ENDOTHELIAL CELL GRANULES
(CALLED WEIBEL-PALADE BODIES) TO THE CELL SURFACE.
REGULATION OF EXPRESSION OF ENDOTHELIAL AND
LEUKOCYTE ADHESION MOLECULES
• A, REDISTRIBUTION OF P-SELECTIN
FROM INTRACELLULAR STORES TO
THE CELL SURFACE.
• B, INCREASED SURFACE
EXPRESSION OF SELECTINS AND
LIGANDS FOR INTEGRINS UPON
CYTOKINE ACTIVATION OF
ENDOTHELIUM.
• C, INCREASED BINDING AVIDITY OF
INTEGRINS INDUCED BY
CHEMOKINES. CLUSTERING OF
INTEGRINS CONTRIBUTES TO THEIR
INCREASED BINDING AVIDITY.
 LEUKOCYTE MIGRATION THROUGH
ENDOTHELIUM
• ALSO CALLED TRANSMIGRATION OR DIAPEDESIS.
CHEMOKINES ACT ON THE ADHERENT
LEUKOCYTES AND STIMULATE THE CELLS TO
MIGRATE TOWARD THE SITE OF INJURY OR
INFECTION WHERE THE CHEMOKINES ARE BEING
PRODUCED.
OCCURS AFTER FIRM ADHESION WITHIN THE
SYSTEM OF VENULES AND CAPILLARIES VIA PECAM-
1(CD31)
(PLATELET ENDOTHELIAL CELL ADHESION
MOLECULE ) ON ENDOTHELIAL CELLS,
NEUTROPHILS, MONOCYTES/MACROPHAGES,AND
THE MULTISTEP PROCESS OF
LEUKOCYTE MIGRATION
THROUGH BLOOD VESSELS
LEUKOCYTE MIGRATION THROUGH ENDOTHELIUM
• AFTER TRAVERSING THE ENDOTHELIUM, LEUKOCYTES PIERCE
THE BASEMENT MEMBRANE, PROBABLY BY SECRETING
COLLAGENASES, AND ENTER THE EXTRAVASCULAR TISSUE.
• THE CELLS THEN MIGRATE TOWARD THE CHEMOTACTIC
GRADIENT CREATED BY CHEMOKINES AND ACCUMULATE IN
THE EXTRAVASCULAR SITE.
 CHEMOTAXIS OF LEUKOCYTES
• AFTER EXITING THE CIRCULATION, LEUKOCYTES EMIGRATE IN
TISSUES TOWARD THE SITE OF INJURY BY A PROCESS CALLED
CHEMOTAXIS.
BOTH EXOGENOUS AND ENDOGENOUS SUBSTANCES CAN ACT AS
CHEMOATTRACTANTS.
 THE MOST COMMON EXOGENOUS AGENTS ARE BACTERIAL
PRODUCTS, INCLUDING PEPTIDES THAT POSSESS AN N-
FORMYLMETHIONINE TERMINAL AMINO ACID, AND SOME LIPIDS.
 ENDOGENOUS CHEMOATTRACTANTS INCLUDE SEVERAL CHEMICAL
MEDIATORS: (1) CYTOKINES, PARTICULARLY THOSE OF THE
CHEMOKINE FAMILY (E.G., IL-8) (2) COMPONENTS OF THE
COMPLEMENT SYSTEM, PARTICULARLY C5A
(3) ARACHIDONIC ACID (AA) METABOLITES, MAINLY LEUKOTRIENE B4
(LTB4).
• ALL THESE CHEMOTACTIC AGENTS BIND TO A SPECIFIC SEVEN-
TRANSMEMBRANE G PROTEIN–COUPLED RECEPTORS ON THE
 CHEMOTAXIS OF LEUKOCYTES

increase cytosolic
Chemotactic calcium and activate
agents binds G These signals induce
small guanosine
protein– triphosphatases of the polymerization of
coupled Rac/Rho/cdc42 actin
receptors
family

increased amounts of
The leukocyte moves by extending
polymerized actin at the
filopodia that pull the back of the cell in
leading edge of the cell and
the direction of extension, much as an
localization
automobile with front-wheel drive is
pulled by the wheels in front of myosin filaments at the
back
SCANNING ELECTRON
MICROGRAPH OF A
MOVING LEUKOCYTE
IN CULTURE
SHOWING A
FILOPODIUM (UPPER
LEFT) AND A TRAILING
.TAIL
 THE NATURE OF THE LEUKOCYTE
INFILTRATE
during • Neutrophils
the first 6 predominate
to 24
hours
• Replaced by
in 24 to Monocytes
48 hours.
 REASONS ACCOUNT FOR THE
EARLY APPEARANCE OF
NEUTROPHILS
 THE ARE MORE NUMEROUS IN THE BLOOD.
 THEY RESPOND MORE RAPIDLY TO CHEMOKINES.
 THEY MAY ATTACH MORE FIRMLY TO THE ADHESION
MOLECULES THAT ARE RAPIDLY INDUCED ON ENDOTHELIAL
CELLS, SUCH AS P- AND E-SELECTINS.
 AFTER ENTERING TISSUES, NEUTROPHILS ARE SHORT-
LIVED; THEY UNDERGO APOPTOSIS AND DISAPPEAR AFTER
24 TO 48 HOURS.
 MONOCYTES NOT ONLY SURVIVE LONGER BUT MAY
PROLIFERATE IN THE TISSUES, AND THUS BECOME THE
DOMINANT POPULATION IN CHRONIC INFLAMMATORY
REACTIONS
EXCEPTIONS TO THIS PATTERN OF
CELLULAR INFILTRATION
• cellular infiltrate is dominated by
Pseudomonas continuously recruited neutrophils for
bacteria several days.

Viral • lymphocytes may be the first cells to arrive

infections

some
hypersensitivity • eosinophils may be the main cell type.
reactions
 RECOGNITION OF MICROBES AND DEAD
TISSUES
• LEUKOCYTES EXPRESS SEVERAL RECEPTORS THAT RECOGNIZE
EXTERNAL STIMULI AND DELIVER ACTIVATING SIGNALS:
 RECOGNITION OF MICROBES AND
DEAD TISSUES
1.RECEPTORS FOR MICROBIAL PRODUCTS: TOLL-LIKE
RECEPTORS (TLRS):
 RECOGNIZE COMPONENTS OF DIFFERENT TYPES OF
MICROBES.
 DIFFERENT TLRS PLAY ESSENTIAL ROLES IN
CELLULAR RESPONSES TO BACTERIAL
LIPOPOLYSACCHARIDE (LPS, OR ENDOTOXIN), OTHER
BACTERIAL PROTEOGLYCANS AND LIPIDS, AND
UNMETHYLATED CPG NUCLEOTIDES.
 TLRS ARE PRESENT ON THE CELL SURFACE AND IN
THE ENDOSOMAL VESICLES OF LEUKOCYTES.
 THEY ARE ABLE TO SENSE PRODUCTS OF
EXTRACELLULAR AND INGESTED MICROBES.
 FUNCTION THROUGH RECEPTOR-ASSOCIATED
KINASES TO STIMULATE THE PRODUCTION OF
MICROBICIDAL SUBSTANCES AND CYTOKINES BY THE
 RECOGNITION OF MICROBES AND DEAD TISSUES
2. G PROTEIN–COUPLED RECEPTORS:
 FOUND ON NEUTROPHILS,
MACROPHAGES, AND MOST OTHER
TYPES OF LEUKOCYTES
 RECOGNIZE SHORT BACTERIAL
PEPTIDES CONTAINING N-
FORMYLMETHIONYL RESIDUES
 ALL BACTERIAL PROTEINS ARE
INITIATED BY N-FORMYLMETHIONINE.
 THIS RECEPTOR ENABLES NEUTROPHILS
TO DETECT AND RESPOND TO
BACTERIAL PROTEINS
 BINDING OF LIGANDS, SUCH AS
MICROBIAL PRODUCTS AND MEDIATORS,
TO THE G PROTEIN–COUPLED
RECEPTORS INDUCES MIGRATION OF
 RECOGNITION OF MICROBES AND
DEAD TISSUES
3. RECEPTORS FOR OPSONINS:
 LEUKOCYTES EXPRESS RECEPTORS FOR
PROTEINS THAT COAT MICROBES
 ONE OF THE MOST EFFICIENT WAYS OF
ENHANCING THE PHAGOCYTOSIS OF
PARTICLES IS COATING THE PARTICLES WITH
IGG ANTIBODIES SPECIFIC FOR THE
PARTICLES, WHICH ARE THEN RECOGNIZED
BY THE HIGH-AFFINITY FCΓ RECEPTOR OF
PHAGOCYTES, CALLED FCΓRI .
 THE BINDING OF OPSONIZED PARTICLES TO
LEUKOCYTE FC PROMOTES PHAGOCYTOSIS
OF THE PARTICLES AND ACTIVATES THE
CELLS.
 RECOGNITION OF MICROBES AND
DEAD TISSUES
4. RECEPTORS FOR CYTOKINES:
 LEUKOCYTES EXPRESS RECEPTORS
FOR CYTOKINES THAT ARE
PRODUCED IN RESPONSE TO
MICROBES.
 ONE OF THE MOST IMPORTANT OF
THESE CYTOKINES IS INTERFERON-
Γ (ΙFN-Γ), WHICH IS SECRETED BY
NATURAL KILLER CELLS REACTING
TO MICROBES AND BY ANTIGEN-
ACTIVATED T LYMPHOCYTES
DURING ADAPTIVE IMMUNE
RESPONSES.
 IFN-Γ IS THE MAJOR MACROPHAGE-
ACTIVATING CYTOKINE.
 REMOVAL OF THE
OFFENDING AGENTS
 THE FUNCTIONAL RESPONSES
THAT ARE MOST IMPORTANT FOR
DESTRUCTION OF MICROBES AND
OTHER OFFENDERS ARE
PHAGOCYTOSIS AND
INTRACELLULAR KILLING.
 DESTRUCTION OF INGESTED
PARTICLES WITHIN THE
PHAGOLYSOSOMES BY LYSOSOMAL
ENZYMES AND BY REACTIVE
OXYGEN AND NITROGEN SPECIES.
 THE MICROBICIDAL PRODUCTS
GENERATED FROM SUPEROXIDE
(O2•− ) ARE HYPOCHLORITE (HOCL)
AND HYDROXYL RADICAL (•OH),
AND FROM NITRIC OXIDE (NO) IT IS
PEROXYNITRITE (OONO•).
 OTHER FUNCTIONAL RESPONSES OF
ACTIVATED LEUKOCYTES

• DIFFERENT STIMULI ACTIVATE MONOCYTES/MACROPHAGES TO DEVELOP INTO

FUNCTIONALLY DISTINCT POPULATIONS:
I. CLASSICALLY ACTIVATED MACROPHAGES: ARE INDUCED BY MICROBIAL
PRODUCTS AND CYTOKINES, PARTICULARLY IFN-Γ, AND ARE MICROBICIDAL
AND INVOLVED IN POTENTIALLY HARMFUL INFLAMMATION.
II. ALTERNATIVELY ACTIVATED MACROPHAGES: ARE INDUCED BY OTHER
CYTOKINES AND IN RESPONSE TO HELMINTHS AND ARE IMPORTANT IN
TISSUE REPAIR AND THE RESOLUTION OF INFLAMMATION
 RELEASE OF LEUKOCYTE PRODUCTS
AND
LEUKOCYTE-MEDIATED TISSUE INJURY
• LEUKOCYTES ARE IMPORTANT CAUSES OF INJURY TO
NORMAL CELLS AND TISSUES UNDER SEVERAL
CIRCUMSTANCES:
A. AS PART OF A NORMAL DEFENSE REACTION AGAINST
INFECTIOUS MICROBES, WHEN ADJACENT TISSUES
SUFFER “COLLATERAL DAMAGE.” AND IN SOME
INFECTIONS THAT ARE DIFFICULT TO ERADICATE, SUCH
AS TUBERCULOSIS AND CERTAIN VIRAL DISEASES, THE
PROLONGED HOST RESPONSE CONTRIBUTES MORE TO
THE PATHOLOGY THAN DOES THE MICROBE ITSELF.
B. AUTOIMMUNE DISEASES: WHEN THE INFLAMMATORY
RESPONSE IS INAPPROPRIATELY DIRECTED AGAINST HOST
TISSUES.
 RELEASE OF LEUKOCYTE PRODUCTS AND
LEUKOCYTE-MEDIATED TISSUE INJURY

 ONCE THE LEUKOCYTES ARE ACTIVATED, THEIR EFFECTOR

MECHANISMS DO NOT DISTINGUISH BETWEEN OFFENDER AND
HOST.
 DURING ACTIVATION AND PHAGOCYTOSIS, NEUTROPHILS AND
MACROPHAGES RELEASE MICROBICIDAL AND OTHER PRODUCTS
NOT ONLY WITHIN THE PHAGOLYSOSOME BUT ALSO INTO THE
EXTRACELLULAR SPACE.
 THE MOST IMPORTANT OF THESE SUBSTANCES ARE LYSOSOMAL
ENZYMES, PRESENT IN THE GRANULES, AND REACTIVE OXYGEN AND
NITROGEN SPECIES.
 THESE RELEASED SUBSTANCES ARE CAPABLE OF DAMAGING
NORMAL CELLS AND VASCULAR ENDOTHELIUM, AND MAY THUS
 DEFECTS IN LEUKOCYTE FUNCTION
 INHERITED OR ACQUIRED.
 LEAD TO INCREASED VULNERABILITY TO INFECTIONS.
• THESE INCLUDE THE FOLLOWING:

I. INHERITED DEFECTS IN LEUKOCYTE ADHESION: GENETIC

DEFECTS OF INTEGRINS AND SELECTIN-LIGANDS LEUKOCYTE
ADHESION DEFICIENCIES TYPES 1 AND 2 RECURRENT
BACTERIAL INFECTIONS.
II. INHERITED DEFECTS IN PHAGOLYSOSOME FUNCTION: CHÉDIAK-
HIGASHI SYNDROME(AR)
III. INHERITED DEFECTS IN MICROBICIDAL ACTIVITY: CHRONIC
GRANULOMATOUS DISEASE INHERITED DEFECTS IN THE GENES
ENCODING COMPONENTS OF PHAGOCYTE OXIDASE, WHICH
GENERATES O2•−.
IV. ACQUIRED DEFICIENCIES: E.G., LEUKEMIAS / RADIATION AND
CHEMOTHERAPYBONE MARROW SUPPRESSIONDECREASED
DEFECTS IN LEUKOCYTE
FUNCTIONS
TERMINATION OF THE ACUTEINFLAMMATORY RESPONSE

• INFLAMMATION DECLINES SIMPLY BECAUSE THE MEDIATORS OF

INFLAMMATION ARE PRODUCED IN RAPID BURSTS, HAVE SHORT HALF-
LIVES, AND ARE DEGRADED AFTER THEIR RELEASE.
• NEUTROPHILS ALSO HAVE SHORT HALF-LIVES IN TISSUES AND DIE BY
APOPTOSIS A FEW HOURS AFTER LEAVING THE BLOOD
• THE PROCESS ALSO TRIGGERS A VARIETY OF STOP SIGNALS THAT
SERVE TO ACTIVELY TERMINATE THE REACTION:

1. active termination
mechanisms include a
switch in the type of proinflammator
arachidonic acid metabolite y leukotrienes
produced, from
proinflammatory anti-
leukotrienes to anti- inflammatory
inflammatory lipoxins lipoxins
 TERMINATION OF THE ACUTE
INFLAMMATORY RESPONSE

2.LIBERATION OF ANTI-
INFLAMMATORY
CYTOKINES, INCLUDING
TRANSFORMING
GROWTH FACTOR-Β (TGF-
Β) AND IL-10, FROM
MACROPHAGES AND
OTHER CELLS
MEDIATORS OF INFLAMMATION
 MEDIATORS OF INFLAMMATION
• MEDIATORS ARE GENERATED EITHER FROM CELLS OR FROM PLASMA PROTEINS.

Cell-derived mediators Plasma-derived

(platelets, neutrophils, mediators
monocytes/macrophages, mast cells, mesenchymal (e.g., complement
cells <endothelium, smooth muscle, fibroblasts> and
most epithelia) proteins, kinins)

activated,
Or are usually by
secreted by present in
a series of
synthesized de the
sequestered granule produced circulatio
proteolyti
novo (e.g., c
exocytosis mainly in n as
in intracellular (e.g., histamine prostaglandins cleavages,
, cytokines) in the liver inactive
granules in mast cell precursor
to acquire
response to a their
granules) s
stimulus biologic
properties
MEDIATORS OF INFLAMMATION
 MEDIATORS OF INFLAMMATION
• ACTIVE MEDIATORS ARE PRODUCED IN RESPONSE TO VARIOUS
STIMULI.(E.G. MICROBIAL PRODUCTS, SUBSTANCES RELEASED FROM
NECROTIC CELLS, THE PROTEINS OF THE COMPLEMENT, KININ, AND
COAGULATION SYSTEMS, WHICH ARE THEMSELVES ACTIVATED BY
MICROBES AND DAMAGED TISSUES.
• ONE MEDIATOR CAN STIMULATE THE RELEASE OF OTHER
MEDIATORS(E.G. CYTOKINE TNF ACTS ON ENDOTHELIAL CELLS
STIMULATE THE PRODUCTION OF ANOTHER CYTOKINE, IL-1, AND
MANY CHEMOKINES).
• MEDIATORS VARY IN THEIR RANGE OF CELLULAR TARGETS(CAN ACT
ON ONE OR A FEW TARGET CELL TYPES, CAN HAVE DIVERSE TARGETS)
• ONCE ACTIVATED AND RELEASED FROM THE CELL, MOST OF THESE
MEDIATORS ARE SHORT-LIVED. THEY QUICKLY DECAY (E.G.,
ARACHIDONIC ACID METABOLITES) OR ARE INACTIVATED BY ENZYMES
(E.G., KININASE INACTIVATES BRADYKININ), OR THEY ARE OTHERWISE
SCAVENGED (E.G., ANTIOXIDANTS SCAVENGE TOXIC OXYGEN
METABOLITES)
 CELL-DERIVED MEDIATORS
VASOACTIVE AMINES: HISTAMINE
AND SEROTONIN
• STORED AS PREFORMED MOLECULES IN CELLS
• THE FIRST MEDIATORS TO BE RELEASED DURING INFLAMMATION
• RICHEST SOURCES OF HISTAMINE ARE THE MAST CELLS THAT ARE
NORMALLY PRESENT IN THE CONNECTIVE TISSUE ADJACENT TO
BLOOD VESSELS. (ALSO FOUND IN BLOOD BASOPHILS AND
PLATELETS).
• RELEASED BY MAST CELL DEGRANULATION IN RESPONSE TO A
VARIETY OF STIMULI: (1) PHYSICAL INJURY SUCH AS TRAUMA, (2)
BINDING OF ANTIBODIES TO MAST CELLS, WHICH UNDERLIES
ALLERGIC REACTIONS ;(3) FRAGMENTS OF COMPLEMENT
CALLED ANAPHYLATOXINS (C3A AND C5A); (4) HISTAMINE-
RELEASING PROTEINS DERIVED FROM LEUKOCYTES; (5)
NEUROPEPTIDES (E.G., SUBSTANCE P); AND (6) CYTOKINES (IL-1,
IL-8)
 CELL-DERIVED MEDIATORS
VASOACTIVE AMINES:
HISTAMINE
• HISTAMINE CAUSES DILATION OF
ARTERIOLES AND INCREASES THE
PERMEABILITY OF VENULES.
• IT IS THE PRINCIPAL MEDIATOR OF
THE IMMEDIATE TRANSIENT PHASE
OF INCREASED VASCULAR
PERMEABILITY, PRODUCING
INTERENDOTHELIAL GAPS IN
VENULES.
• ITS VASOACTIVE EFFECTS ARE
MEDIATED MAINLY VIA BINDING TO
 CELL-DERIVED MEDIATORS
VASOACTIVE AMINES: SEROTONIN
(5-HYDROXYTRYPTAMINE)

• PREFORMED VASOACTIVE MEDIATOR

• IT IS PRESENT IN PLATELETS AND CERTAIN NEUROENDOCRINE
CELLS
• RELEASE OF SEROTONIN (AND HISTAMINE) FROM PLATELETS IS
STIMULATED WHEN PLATELETS AGGREGATE AFTER CONTACT
WITH COLLAGEN, THROMBIN, ADENOSINE DIPHOSPHATE, AND
ANTIGEN-ANTIBODY COMPLEXES
• THE PLATELET RELEASE REACTION, WHICH IS A KEY
COMPONENT OF COAGULATION, ALSO RESULTS IN INCREASED
VASCULAR PERMEABILITY. THIS IS ONE OF SEVERAL LINKS
BETWEEN CLOTTING AND INFLAMMATION.
 ARACHIDONIC ACID (AA) METABOLITES:
PROSTAGLANDINS, LEUKOTRIENES,
AND LIPOXINS
 CELLS ARE ACTIVATED BY DIVERSE STIMULI( SUCH AS MICROBIAL
PRODUCTS AND VARIOUS MEDIATORS OF INFLAMMATION)
MEMBRANE AA IS RAPIDLY CONVERTED BY THE ACTIONS OF
ENZYMES TO PRODUCE PROSTAGLANDINS AND LEUKOTRIENES.
SERVE AS INTRACELLULAR OR EXTRACELLULAR SIGNALS
TO AFFECT A VARIETY OF BIOLOGIC PROCESSES, INCLUDING
INFLAMMATION AND HEMOSTASIS.
 ARACHIDONIC ACID (AA)
METABOLITES:
PROSTAGLANDINS, LEUKOTRIENES,
AND LIPOXINS
• AA-DERIVED MEDIATORS, ALSO CALLED
EICOSANOIDS, ARE SYNTHESIZED BY TWO MAJOR
CLASSES OF ENZYMES: CYCLOOXYGENASES
(WHICH GENERATE PROSTAGLANDINS) AND
LIPOXYGENASES (WHICH PRODUCE
LEUKOTRIENES AND LIPOXINS) .
• EICOSANOIDS BIND TO G PROTEIN–COUPLED
RECEPTORS ON MANY CELL TYPES AND CAN
MEDIATE VIRTUALLY EVERY STEP OF
INFLAMMATION
 PROSTAGLANDINS (PGS)

• PRODUCED BY MAST CELLS, MACROPHAGES, ENDOTHELIAL

CELLS, AND MANY OTHER CELL TYPES.
• PRODUCED BY THE ACTIONS OF TWO CYCLOOXGENASES,
CONSTITUTIVELY EXPRESSED COX-1 AND THE INDUCIBLE
ENZYME COX-2.
• PROSTAGLANDINS ARE DIVIDED INTO SERIES BASED ON

STRUCTURAL FEATURES AS CODED BY A LETTER (PG D, PGE,

PGF, PGG, AND PGH) AND A SUBSCRIPT NUMERAL (E.G., 1, 2),
WHICH INDICATES THE NUMBER OF DOUBLE BONDS IN THE
COMPOUND.
• PGD2 IS THE MAJOR PROSTAGLANDIN MADE BY MAST CELLS;
ALONG WITH PGE2 (WHICH IS MORE WIDELY DISTRIBUTED), IT
CAUSES VASODILATION AND INCREASES THE PERMEABILITY
OF POST-CAPILLARY VENULES, THUS POTENTIATING EDEMA
 PROSTAGLANDINS (PGS)
• PGF2Α STIMULATES THE CONTRACTION OF UTERINE AND
BRONCHIAL SMOOTH MUSCLE AND SMALL ARTERIOLES,
AND PGD2 IS A CHEMOATTRACTANT FOR NEUTROPHILS.
• THE PROSTAGLANDINS ARE INVOLVED IN THE
PATHOGENESIS OF PAIN AND FEVER IN INFLAMMATION.
• PGE2 IS HYPERALGESIC AND MAKES THE SKIN
HYPERSENSITIVE TO PAINFUL STIMULI, SUCH AS
INTRADERMAL INJECTION OF SUBOPTIMAL
CONCENTRATIONS OF HISTAMINE AND BRADYKININ. IT
IS INVOLVED IN CYTOKINE-INDUCED FEVER DURING
INFECTIONS
 LEUKOTRIENES
 5-LIPOXYGENASE ENZYME CONVERTS AA TO THE
PRECURSOR OF THE LEUKOTRIENES.
 LTB4 IS A POTENT CHEMOTACTIC AGENT AND ACTIVATOR OF
NEUTROPHILS, CAUSING AGGREGATION AND ADHESION OF
THE CELLS TO VENULAR ENDOTHELIUM, GENERATION OF
ROS, AND RELEASE OF LYSOSOMAL ENZYMES.
 THE CYSTEINYL CONTAINING LEUKOTRIENES C4, D4, AND E4
(LTC4, LTD4, LTE4) CAUSE INTENSE VASOCONSTRICTION,
BRONCHOSPASM (IMPORTANT IN ASTHMA), AND INCREASED
VASCULAR PERMEABILITY.
 LEUKOTRIENES ARE MUCH MORE POTENT THAN IS
HISTAMINE IN INCREASING VASCULAR PERMEABILITY AND
CAUSING BRONCHOSPASM.
 LIPOXINS
• GENERATED FROM AA BY THE LIPOXYGENASE
PATHWAY.
• UNLIKE PROSTAGLANDINS AND LEUKOTRIENES, THE
LIPOXINS ARE INHIBITORS OF INFLAMMATION.
• THEY ARE UNUSUAL IN THAT TWO CELL
POPULATIONS ARE REQUIRED FOR THE
TRANSCELLULAR BIOSYNTHESIS OF THESE
MEDIATORS.
• THE PRINCIPAL ACTIONS OF LIPOXINS ARE TO INHIBIT
LEUKOCYTE RECRUITMENT AND THE CELLULAR
COMPONENTS OF INFLAMMATION.
• INVERSE RELATIONSHIP BETWEEN THE PRODUCTION
OF LIPOXIN AND LEUKOTRIENES, THAT THE LIPOXINS
 ANTI-INFLAMMATORY DRUGS WORK BY
INHIBITING THE SYNTHESIS OF
EICOSANOIDS
CYCLOOXYGENASE INHIBITORS:
• ASPIRIN AND OTHER
NONSTEROIDAL ANTI-
INFLAMMATORY DRUGS
(NSAIDS), SUCH AS
INDOMETHACIN.
• THEY INHIBIT BOTH COX-1
AND COX-2  INHIBIT
PROSTAGLANDIN
SYNTHESIS; ASPIRIN DOES
THIS BY IRREVERSIBLY
ACETYLATING AND
INACTIVATING
CYCLOOXYGENASES.
 ANTI-INFLAMMATORY DRUGS WORK BY
INHIBITING THE SYNTHESIS OF
EICOSANOIDS
LIPOXYGENASE INHIBITORS:
• 5-LIPOXYGENASE IS NOT
AFFECTED BY NSAIDS.
• PHARMACOLOGIC AGENTS
THAT INHIBIT LEUKOTRIENE
PRODUCTION (E.G.
ZILEUTON) OR BLOCK
LEUKOTRIENE RECEPTORS
(E.G. MONTELUKAST) ARE
USEFUL IN THE TREATMENT
OF ASTHMA.
 ANTI-INFLAMMATORY DRUGS
WORK BY INHIBITING THE
SYNTHESIS OF EICOSANOIDS
BROAD-SPECTRUM INHIBITORS INCLUDE
CORTICOSTEROIDS:
• THESE POWERFUL ANTI-INFLAMMATORY AGENTS MAY
ACT BY REDUCING THE TRANSCRIPTION OF GENES
ENCODING COX-2, PHOSPHOLIPASE A2, PRO-INFL
AMMATORY CYTOKINES (SUCH AS IL-1 AND TNF), AND
INOS.
 ANOTHER APPROACH TO MANIPULATING
INFLAMMATORY RESPONSES :
• BY MODIFYING THE INTAKE AND CONTENT OF DIETARY
LIPIDS BY INCREASING THE CONSUMPTION OF FISH OIL.
the polyunsaturated
fatty acids in fish oil
. as poor
serve
substrates for
conversion to active
metabolites by both the
cyclooxygenase and
lipoxygenase pathways
but are excellent
substrates for the
production of anti-
inflammatory lipid
products called
resolvins and
PLATELET-ACTIVATING FACTOR (PAF)
 ANOTHER PHOSPHOLIPID-DERIVED MEDIATOR.
 MULTIPLE INFLAMMATORY EFFECTS.
 PRODUCED BY A VARIETY OF CELL TYPES, INCLUDING
PLATELETS THEMSELVES, BASOPHILS, MAST CELLS,
NEUTROPHILS, MACROPHAGES, AND ENDOTHELIAL CELLS.
 PAF CAUSES : PLATELET AGGREGATION, VASOCONSTRICTION
AND BRONCHOCONSTRICTION, AND AT EXTREMELY LOW
CONCENTRATIONS IT INDUCES VASODILATION AND
INCREASED VENULAR PERMEABILITY WITH A POTENCY 100 TO
10,000 TIMES GREATER THAN THAT OF HISTAMINE.
 PAF ALSO CAUSES INCREASED LEUKOCYTE ADHESION TO
ENDOTHELIUM (BY ENHANCING INTEGRIN-MEDIATED
LEUKOCYTE BINDING), CHEMOTAXIS, DEGRANULATION, AND
THE OXIDATIVE BURST.
 REACTIVE OXYGEN SPECIES

• RELEASED EXTRACELLULARLY FROM LEUKOCYTES AFTER

EXPOSURE TO MICROBES, CHEMOKINES, AND IMMUNE
COMPLEXES, OR FOLLOWING A PHAGOCYTIC CHALLENGE.
• THEIR PRODUCTION IS DEPENDENT, ON THE ACTIVATION OF
THE NADPH OXIDASE SYSTEM.
• SUPEROXIDE ANION (O2•−), HYDROGEN PEROXIDE (H2O2),
AND HYDROXYL RADICAL (•OH) ARE THE MAJOR SPECIES
PRODUCED WITHIN CELLS, AND O2•− CAN COMBINE WITH
NO TO FORM REACTIVE NITROGEN SPECIES
• IMPLICATED IN THE FOLLOWING RESPONSES IN
INFLAMMATION:
Endothelial cell damage, with
• Adherent neutrophils, when activated, not only
resultant increased vascular produce their own toxic species but also stimulate
permeability. production of ROS in the endothelial cells.

Injury to other • (parenchymal cells, red blood cells)

cell types

Inactivation of • unopposed protease activity, with increase

destruction of extracellular matrix
antiproteases, • In the lung, such inhibition of anti-proteases
such as α1- contributes to destruction of elastic tissues, as in
antitrypsin. emphysema
 ANTIOXIDANT MECHANISMS
• TISSUE FLUIDS, AND HOST CELLS POSSESS
ANTIOXIDANT MECHANISMS THAT PROTECT AGAINST
THESE POTENTIALLY HARMFUL OXYGEN-DERIVED
RADICALS.
The enzyme The enzyme
superoxide catalase (detoxifies
dismutase H2O2)

Glutathione The copper-

peroxidase(another containing serum
powerful H2O2 protein
detoxifier) ceruloplasmin

the iron-free
fraction of serum
transferrin.
 NITRIC OXIDE (NO)
 NO IS A SOLUBLE GAS
 PRODUCED BY ENDOTHELIAL
CELLS, MACROPHAGES AND
SOME NEURONS IN THE BRAIN.
 IT ACTS IN A PARACRINE
MANNER ON TARGET CELLS
THROUGH INDUCTION OF
CYCLIC GUANOSINE
MONOPHOSPHATE, WHICH, IN
TURN, INITIATES A SERIES OF
INTRACELLULAR EVENTS
LEADING TO A RESPONSE, SUCH
AS THE RELAXATION OF
VASCULAR SMOOTH MUSCLE
CELLS.
 THE IN VIVO HALF-LIFE OF NO
IS ONLY SECONDS, THE GAS
ACTS ONLY ON CELLS IN CLOSE
 NO IS SYNTHESIZED FROM L-
ARGININE BY THE ENZYME
NITRIC OXIDE SYNTHASE
(NOS).
 THERE ARE THREE DIFFERENT
TYPES OF NOS: ENDOTHELIAL
(ENOS), NEURONAL (NNOS),
AND INDUCIBLE (INOS)
 NO HAS DUAL ACTIONS IN
INFLAMMATION: IT RELAXES
VASCULAR SMOOTH MUSCLE
AND PROMOTES
VASODILATION, THUS
CONTRIBUTING TO THE
VASCULAR REACTION, BUT IT
IS ALSO AN INHIBITOR OF THE
CELLULAR COMPONENT OF
 CYTOKINES AND CHEMOKINES

• PROTEINS PRODUCED BY MANY CELL TYPES (PRINCIPALLY ACTIVATED

LYMPHOCYTES ,MACROPHAGES, AND ENDOTHELIAL, EPITHELIAL, CONNECTIVE
TISSUE CELLS) THAT MODULATE THE FUNCTIONS OF OTHER CELL TYPES.
PRINCIPAL LOCAL AND SYSTEMIC ACTIONS
OF TUMOR NECROSIS FACTOR (TNF) AND
INTERLEUKIN-1 (IL-1)
 LYSOSOMAL CONSTITUENTS OF LEUKOCYTES
•Neutrophils and monocytes contain lysosomal granules, which,
when released, may contribute to the inflammatory response.
• BECAUSE OF THE DESTRUCTIVE EFFECTS
OF LYSOSOMAL ENZYMES, THE INITIAL
LEUKOCYTIC INFILTRATION, IF
UNCHECKED, CAN POTENTIATE FURTHER
INFLAMMATION AND TISSUE DAMAGE.
• THESE HARMFUL PROTEASES, ARE HELD
IN CHECK BY A SYSTEM OF
ANTIPROTEASES IN THE SERUM AND
TISSUE FUIDS.
• AMONG THESE IS Α1-ANTITRYPSIN,
WHICH IS THE MAJOR INHIBITOR OF
NEUTROPHIL ELASTASE. A DEFICIENCY
OF THESE INHIBITORS MAY LEAD TO
SUSTAINED ACTION OF LEUKOCYTE
PROTEASES, AS IS THE CASE IN PATIENTS
WITH Α1-ANTITRYPSIN DEFICIENCY
 NEUROPEPTIDES
• NEUROPEPTIDES ARE SECRETED BY SENSORY NERVES AND VARIOUS
LEUKOCYTES, AND PLAY A ROLE IN THE INITIATION AND
PROPAGATION OF INFLAMMATORY RESPONSE.

• THE SMALL PEPTIDES, SUCH AS SUBSTANCE P AND NEUROKININ A,

BELONG TO A FAMILY OF TACHYKININ NEUROPEPTIDES PRODUCED IN
THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS.

• NERVE FIBERS CONTAINING SUBSTANCE P ARE PROMINENT IN THE

LUNG AND GASTROINTESTINAL TRACT.
• SUBSTANCE P HAS MANY BIOLOGIC FUNCTIONS, INCLUDING THE
TRANSMISSION OF PAIN SIGNALS, REGULATION OF BLOOD PRESSURE,
STIMULATION OF SECRETION BY ENDOCRINE CELLS, AND INCREASING
VASCULAR PERMEABILITY.
 PLASMA PROTEIN–DERIVED MEDIATORS

• THREE INTERRELATED SYSTEMS: THE

COMPLEMENT, KININ, AND CLOTTING SYSTEMS.

Complement

Kinin

clotting
systems
 COMPLEMENT SYSTEM
• >20 PROTEINS
• C1-C9

chemotaxis

Increased
vascular opsonization
permeability

Complemen
t
 THE ACTIVATION AND FUNCTIONS OF THE
COMPLEMENT SYSTEM

Activation of complement by different pathways leads to cleavage of C3.

The functions of the complement system are mediated by breakdown
products of C3 and other complement proteins, and by the membrane attack
complex (MAC).
 THE CLASSICAL
PATHWAY

• TRIGGERED BY
FIXATION OF C1 TO
ANTIBODY (IGM OR
IGG) THAT HAS
COMBINED WITH
ANTIGEN
 ALTERNATIVE PATHWAY

CAN BE TRIGGERED BY:

• MICROBIAL SURFACE
MOLECULES (E.G.,
ENDOTOXIN, OR LPS),
COMPLEX
POLYSACCHARIDES,
COBRA VENOM, AND
OTHER SUBSTANCES,
IN THE ABSENCE OF
ANTIBODY
 THE LECTIN PATHWAY
• PLASMA MANNOSE-BINDING LECTIN BINDS TO
CARBOHYDRATES ON MICROBES AND DIRECTLY
ACTIVATES C1.
 OVERVIEW OF THE COMPLEMENT SYSTEM
All pathways lead to the
formation of an active enzyme
called the C3 convertase, which
splits C3 into two functionally
distinct fragments, C3a and C3b.

C3a is released, and C3b

becomes covalently attached to
the cell or molecule where
complement is being activated.

 More C3b then binds to the

previously generated fragments
to form C5 convertase, which
cleaves C5 to release C5a and
leave C5b attached to the cell
surface.

 C5b binds the late components

(C6–C9), culminating in the
formation of the membrane
attack complex (MAC, composed
of multiple C9 molecules)
 COAGULATION AND KININ SYSTEMS
• INFLAMMATION AND BLOOD CLOTTING ARE OFTEN INTERTWINED, WITH
EACH PROMOTING THE OTHER.
• THE CLOTTING SYSTEM IS DIVIDED INTO TWO PATHWAYS THAT CONVERGE:
THE ACTIVATION OF THROMBIN AND THE FORMATION OF FIBRIN

XIIa is inducing
fibrin clot
formation, and
activates the
fbrinolytic system.
This cascade
counterbalances
clotting by cleaving
fibrin, thereby
solubilizing
the clot.
activated upon contact
with negatively charged
surfaces when vascular
permeability increases
and plasma proteins leak
into the extravascular
space and come into
contact with collagen, or
when it comes into
contact with basement
membranes exposed as a
result of endothelial
damage.
 KININS
 Kinins are vasoactive peptides derived from plasma proteins,
called kininogens, by the action of specific proteases called
kallikreins.
 Bradykinin increases
vascular permeability and
causes contraction of
smooth muscle, dilation of
blood vessels, and pain
when injected into the
skin. These effects are
similar to those of
histamine.
 The action of
bradykinin
is short-lived, because it
is quickly inactivated by
 CONCLUSIONS
• BRADYKININ, C3A, AND C5A (AS MEDIATORS OF INCREASED VASCULAR
PERMEABILITY); C5A (AS THE MEDIATOR OF CHEMOTAXIS);AND THROMBIN
(WHICH HAS EFFECTS ON ENDOTHELIAL CELLS AND MANY OTHER CELL TYPES)
ARE LIKELY TO BE THE MOST IMPORTANT IN VIVO.
• C3A AND C5A CAN BE GENERATED BY SEVERAL TYPES OF REACTIONS: (1)
IMMUNOLOGIC REACTIONS, INVOLVING ANTIBODIES AND COMPLEMENT (THE
CLASSICAL PATHWAY); (2) ACTIVATION OF THE ALTERNATIVE AND LECTIN
COMPLEMENT PATHWAYS BY MICROBES, IN THE ABSENCE OF ANTIBODIES; AND
(3) AGENTS NOT DIRECTLY RELATED TO IMMUNE RESPONSES, SUCH AS PLASMIN,
KALLIKREIN, AND SOME SERINE PROTEASES FOUND IN NORMAL TISSUE.
• ACTIVATED HAGEMAN FACTOR (FACTOR XIIA) INITIATES FOUR SYSTEMS INVOLVED
IN THE INFLAMMATORY RESPONSE: (1) THE KININ SYSTEM, WHICH PRODUCES
VASOACTIVE KININS; (2) THE CLOTTING SYSTEM, WHICH INDUCES FORMATION OF
THROMBIN, WHICH HAS INFLAMMATORY PROPERTIES; (3) THE FIBRINOLYTIC
SYSTEM, WHICH PRODUCES PLASMIN AND DEGRADES FIBRIN TO PRODUCE
FIBRINOPEPTIDES, WHICH INDUCE INFLAMMATION; AND (4) THE COMPLEMENT
SYSTEM, WHICH PRODUCES ANAPHYLATOXINS AND OTHER MEDIATORS. SOME OF
THE PRODUCTS OF THIS INITIATION—PARTICULARLY KALLIKREIN—CAN, BY
FEEDBACK, ACTIVATE HAGEMAN FACTOR, RESULTING IN AMPLIFICATION OF
THE REACTION.
ROLE OF MEDIATORS IN DIFFERENT REACTIONS OF
INFLAMMATION
 OUTCOMES OF ACUTE INFLAMMATION
Healing by
connective tissue
Complete resolution replacement Chronic inflammation
(fibrosis/organization
)
occurs after the acute inflammatory
substantial tissue response cannot be
eliminating the destruction, when the resolved, as a result of
either the persistence of
injurious inflammatory injury the injurious agent or
involves tissues that
stimulus are incapable of
some interference with
the normal process of
regeneration healing

abundant fibrin e.g.

removal of cellular exudation in tissue
debris and microbes pneumoniachroni
or serous cavities c lung abscess
by macrophages, (pleura,
and resorption of peritoneum) that Peptic ulcer of the
edema fluid by cannot be duodenum or
lymphatics adequately cleared. stomach
 MORPHOLOGIC PATTERNS OF ACUTE
INFLAMMATION
• THE MORPHOLOGIC HALLMARKS OF ALL ACUTE
INFLAMMATORY REACTIONS ARE DILATION OF
SMALL BLOOD VESSELS, SLOWING OF BLOOD FLOW,
AND ACCUMULATION OF LEUKOCYTES AND FLUID IN
THE EXTRAVASCULAR TISSUE.
 SEROUS INFLAMMATION
• MARKED BY THE OUTPOURING OF A THIN FLUID
THAT MAY BE DERIVED FROM THE PLASMA OR FROM
THE SECRETIONS OF MESOTHELIAL CELLS LINING
THE PERITONEAL, PLEURAL, AND PERICARDIAL
CAVITIES.
• ACCUMULATION OF FLUID IN THESE CAVITIES IS
CALLED AN EFFUSION.
The skin blister resulting from
a burn or viral infection
represents a large accumulation
of serous fluid, either within or
immediately beneath the
epidermis of the skin.
 FIBRINOUS INFLAMMATION
 WITH GREATER INCREASE IN VASCULAR PERMEABILITY, LARGE MOLECULES
SUCH AS FIBRINOGEN PASS THE VASCULAR BARRIER, AND FIBRIN IS FORMED
AND DEPOSITED IN THE EXTRACELLULAR SPACE.
 A FIBRINOUS EXUDATE DEVELOPS WHEN THE VASCULAR LEAKS ARE LARGE
OR THERE IS A LOCAL PROCOAGULANT STIMULUS (E.G., CANCER CELLS).
 A FIBRINOUS EXUDATE IS CHARACTERISTIC OF INFLAMMATION IN THE LINING
OF BODY CAVITIES, SUCH AS THE MENINGES, PERICARDIUM AND PLEURA.
 HISTOLOGICALLY, FIBRIN APPEARS AS AN EOSINOPHILIC MESHWORK OF
THREADS OR SOMETIMES AS AN AMORPHOUS COAGULUM.
 FIBRINOUS EXUDATES MAY BE REMOVED BY FIBRINOLYSIS AND CLEARING OF
OTHER DEBRIS BY MACROPHAGES.
 IF THE FIBRIN IS NOT REMOVED OVER TIME IT MAY STIMULATE THE
INGROWTH OF FIBROBLASTS AND BLOOD VESSELS AND THUS LEAD TO
SCARRING.
 SUPPURATIVE OR PURULENT
INFLAMMATION;ABSCESS
• CHARACTERIZED BY THE PRODUCTION OF LARGE AMOUNTS OF
PUS OR PURULENT EXUDATE CONSISTING OF NEUTROPHILS,
LIQUEFACTIVE NECROSIS, AND EDEMA FLUID.
• PRODUCED BY PYOGENIC (PUS-PRODUCING) BACTERIA (E.G.,
STAPHYLOCOCCI)
• COMMON EXAMPLE OF AN ACUTE SUPPURATIVE INFLAMMATION IS
ACUTE APPENDICITIS.
 ABSCESSES :
 ARE LOCALIZED COLLECTIONS OF PURULENT INFLAMMATORY TISSUE
CAUSED BY SUPPURATION
 PRODUCED BY DEEP SEEDING OF PYOGENIC BACTERIA INTO A
TISSUE
Abscesses have a central region that appears as a
mass of necrotic leukocytes and tissue cells. around
this necrotic focus a zone of preserved neutrophils,
and outside this region vascular dilation and
parenchymal and fbroblastic proliferation occur.
 ULCERS

• AN ULCER IS A LOCAL DEFECT, OR EXCAVATION, OF THE SURFACE OF AN

ORGAN OR TISSUE THAT IS PRODUCED BY THE SLOUGHING (SHEDDING) OF
INFLAMED NECROTIC TISSUE
• CAN OCCUR ONLY WHEN TISSUE NECROSIS AND RESULTANT
INFLAMMATION EXIST ON OR NEAR A SURFACE
MOST COMMONLY ENCOUNTERED IN:
(1) THE MUCOSA OF THE MOUTH, STOMACH, INTESTINES, OR
GENITOURINARY TRACT.
(2) THE SKIN AND SUBCUTANEOUS TISSUE OF THE LOWER EXTREMITIES IN
OLDER PERSONS WHO HAVE CIRCULATORY DISTURBANCES THAT
PREDISPOSE TO EXTENSIVE ISCHEMIC NECROSIS.
• ULCERATIONS ARE BEST EXEMPLIFIED BY PEPTIC ULCER OF THE
STOMACH OR DUODENUM, IN WHICH ACUTE AND CHRONIC
INFLAMMATION COEXIST.
• DURING THE ACUTE STAGE THERE IS INTENSE POLYMORPHONUCLEAR
INFILTRATION AND VASCULAR DILATION IN THE MARGINS OF THE
 SUMMARY OF ACUTE INFLAMMATION
THE SEQUENCE OF EVENTS

The host encounters an injurious agent, such as an infectious microbe

or dead cells.
phagocytes that reside in all tissues try to eliminate these agents.
At the same time phagocytes and other host cells react to the presence
of the foreign or abnormal substance by liberating cytokines, lipid
messengers, and other mediators of inflammation.

Some of these mediators act on small blood vessels and

promote the efflux of plasma and the recruitment of
circulating leukocytes to the site where the offending agent is
located.
The recruited leukocytes are activated by the injurious agent
and by locally produced mediators, and the activated
leukocytes try to remove the offending agent by phagocytosis

As the injurious agent is eliminated and antiinflammatory

mechanisms become active, the process subsides and the host
returns to a normal state of health. If the injurious agent
cannot be quickly eliminated, the result may be chronic
inflammation.
 THE CLINICAL AND PATHOLOGIC MANIFESTATIONS OF
THE INFLAMMATORY RESPONSE
The vascular phenomena
(redness (rubor), warmth
(calor), and swelling
(tumor)
• increased blood flow to the
injured area, resulting
mainly from arteriolar
dilation and opening of
capillary beds induced by
mediators such as
histamine.
• Increased vascular
permeability results in the
accumulation of protein
rich extravascular fluid,
which forms the exudate.
Circulating leukocytes
• Initially predominantly
neutrophils, adhere to the
endothelium via adhesion
molecules, traverse the
endothelium, and migrate
to the site of injury under
the influence of
chemotactic agents.
• Leukocytes are activated
by the offending agent and
by endogenous mediators.
tissue damage
(pain)
• Activated Leukocytes may
release toxic metabolites
and proteases
extracellularly, causing
tissue damage.
• During the damage, and
in part as a result of the
liberation of
prostaglandins,
neuropeptides, and
cytokines, one of the local
symptoms is pain (dolor).
 CHRONIC INFLAMMATION
• PROLONGED DURATION (WEEKS OR MONTHS)
• CAUSES :
I. PERSISTENT INFECTIONS BY MICROORGANISMS THAT ARE
DIFFICULT TO ERADICATE. E.G. MYCOBACTERIA, AND CERTAIN
VIRUSES, FUNGI, AND PARASITES.
II. IMMUNE-MEDIATED INFLAMMATORY DISEASES: IN THESE DISEASES,
AUTOANTIGENS EVOKE A SELF-PERPETUATING IMMUNE REACTION
THAT RESULTS IN CHRONIC TISSUE DAMAGE AND
INFLAMMATION :E.G.
 AUTOIMMUNE DISEASES :RHEUMATOID ARTHRITIS AND MULTIPLE
SCLEROSIS
 UNREGULATED IMMUNE RESPONSES AGAINST MICROBES, AS IN
INFLAMMATORY BOWEL DISEASE.
 ALLERGIC DISEASES :IMMUNE RESPONSES AGAINST COMMON
ENVIRONMENTAL SUBSTANCES , SUCH AS BRONCHIAL ASTHMA
III. PROLONGED EXPOSURE TO POTENTIALLY TOXIC AGENTS, EITHER
EXOGENOUS OR ENDOGENOUS. E.G. SILICOSIS
 MORPHOLOGIC FEATURES

• INFILTRATION WITH MONONUCLEAR CELLS, WHICH INCLUDE

MACROPHAGES, LYMPHOCYTES, AND PLASMA CELLS

• TISSUE DESTRUCTION, INDUCED BY THE PERSISTENT OFFENDING

AGENT OR BY THE INFLAMMATORY CELLS

• ATTEMPTS AT HEALING BY CONNECTIVE TISSUE REPLACEMENT OF

DAMAGED TISSUE, ACCOMPLISHED BY PROLIFERATION OF SMALL
BLOOD VESSELS (ANGIOGENESIS) AND, IN PARTICULAR, FIBROSIS
 ROLE OF MACROPHAGES IN
CHRONIC INFLAMMATION
 THE MACROPHAGE IS THE DOMINANT CELLULAR PLAYER IN
CHRONIC INFLAMMATION .
 ELIMINATE INJURIOUS AGENTS SUCH AS MICROBES.
 INITIATE THE PROCESS OF REPAIR.
 RESPONSIBLE FOR MUCH OF THE TISSUE INJURY IN CHRONIC
INFLAMMATION.
 THE ROLES OF
ACTIVATED
MACROPHAGES IN
CHRONIC
.INFLAMMATION
• MACROPHAGES ARE ACTIVATED BY
NONIMMUNOLOGIC STIMULI SUCH
AS ENDOTOXIN OR BY CYTOKINES
FROM IMMUNE-ACTIVATED T CELLS
(PARTICULARLY IFN-Γ).

• IN SHORT-LIVED INFLAMMATION,
IF THE IRRITANT IS ELIMINATED,
MACROPHAGES EVENTUALLY
DISAPPEAR (EITHER DYING OFF OR
MAKING THEIR WAY INTO THE
LYMPHATICS AND LYMPH NODES).

• IN CHRONIC INFLAMMATION,
MACROPHAGE ACCUMULATION
PERSISTS, AS A RESULT OF
CONTINUOUS RECRUITMENT FROM
THE CIRCULATION AND LOCAL
PROLIFERATION AT THE SITE OF
INFLAMMATION
 OTHER CELLS IN CHRONIC
INFLAMMATION
LYMPHOCYTES

• MOBILIZED IN BOTH ANTIBODY-MEDIATED AND CELL-MEDIATED

IMMUNE REACTIONS.
• ANTIGEN-STIMULATED T AND B CELLS USE VARIOUS ADHESION
MOLECULE PAIRS (SELECTINS, INTEGRINS AND THEIR LIGANDS)
AND CHEMOKINES TO MIGRATE INTO INFLAMMATORY SITES.
• CYTOKINES FROM ACTIVATED MACROPHAGES, MAINLY TNF, IL-1,
AND CHEMOKINES, PROMOTE LEUKOCYTE RECRUITMENT,
SETTING THE STAGE FOR PERSISTENCE OF THE INFLAMMATORY
RESPONSE.
• LYMPHOCYTES AND MACROPHAGES INTERACT IN A
BIDIRECTIONAL WAY: MACROPHAGES DISPLAY ANTIGENS TO T
CELLS AND PRODUCE MEMBRANE MOLECULES (COSTIMULATORS)
AND CYTOKINES (NOTABLY IL-12) THAT STIMULATE T-CELL
RESPONSES
 MACROPHAGE-LYMPHOCYTE
INTERACTIONS IN CHRONIC
.INFLAMMATION
• ACTIVATED T CELLS
PRODUCE CYTOKINES THAT
RECRUIT MACROPHAGES
(TNF, IL-17, CHEMOKINES)
AND OTHERS THAT ACTIVATE
MACROPHAGES (IFNΓ).
DIFFERENT SUBSETS OF T
CELLS (CALLED TH1 AND
TH17) MAY PRODUCE
DIFFERENT SETS OF
CYTOKINES.
• ACTIVATED MACROPHAGES
IN TURN STIMULATE T CELLS
BY PRESENTING ANTIGENS
AND VIA CYTOKINES (SUCH
AS IL-12).
 OTHER CELLS IN CHRONIC
INFLAMMATION
EOSINOPHILS
• ABUNDANT IN IMMUNE REACTIONS MEDIATED BY IGE AND IN
PARASITIC INFECTIONS.

• A CHEMOKINE THAT IS ESPECIALLY IMPORTANT FOR EOSINOPHIL

RECRUITMENT IS EOTAXIN.

• EOSINOPHILS HAVE GRANULES THAT CONTAIN MAJOR BASIC

PROTEIN, A HIGHLY CATIONIC PROTEIN THAT IS TOXIC TO PARASITES
BUT ALSO CAUSES LYSIS OF MAMMALIAN EPITHELIAL CELLS.

• THIS IS WHY EOSINOPHILS ARE OF BENEFIT IN CONTROLLING

PARASITIC INFECTIONS, BUT THEY CONTRIBUTE TO TISSUE
DAMAGE IN IMMUNE REACTIONS SUCH AS ALLERGIES.
A FOCUS OF INFLAMMATION SHOWING NUMEROUS
EOSINOPHILS
 OTHER CELLS IN CHRONIC
INFLAMMATION MAST CELLS
• WIDELY DISTRIBUTED IN CONNECTIVE TISSUES.
• PARTICIPATE IN BOTH ACUTE AND CHRONIC INFLAMMATORY
REACTIONS.
• EXPRESS ON THEIR SURFACE THE RECEPTOR (FCΕRI) THAT BINDS
THE FC PORTION OF IGE ANTIBODY.
• IN IMMEDIATE HYPERSENSITIVITY REACTIONS, IGE ANTIBODIES
BOUND TO THE CELLS’ FC RECEPTORS SPECIFICALLY RECOGNIZE
ANTIGEN, AND THE CELLS DEGRANULATE AND RELEASE
MEDIATORS, SUCH AS HISTAMINE AND PROSTAGLANDINS .
• THIS TYPE OF RESPONSE OCCURS DURING ALLERGIC REACTIONS TO
FOODS, INSECT VENOM, OR DRUGS, SOMETIMES WITH
CATASTROPHIC RESULTS (E.G. ANAPHYLACTIC SHOCK).
• THEY SECRETE A PLETHORA OF CYTOKINES, THAT HAVE THE
ABILITY TO BOTH PROMOTE AND LIMIT INFLAMMATORY
REACTIONS IN DIFFERENT SITUATIONS.
 OTHER CELLS IN CHRONIC
INFLAMMATION NEUTROPHILS
 ALTHOUGH NEUTROPHILS ARE CHARACTERISTIC OF ACUTE
INFLAMMATION, MANY FORMS OF CHRONIC
INFLAMMATION, LASTING FOR MONTHS, CONTINUE TO
SHOW LARGE NUMBERS OF NEUTROPHILS.
 INDUCED EITHER BY PERSISTENT MICROBES OR BY
MEDIATORS PRODUCED BY ACTIVATED MACROPHAGES AND
T LYMPHOCYTES.
 IN CHRONIC BACTERIAL INFECTION OF BONE
(OSTEOMYELITIS), A NEUTROPHILIC EXUDATE CAN PERSIST
FOR MANY MONTHS.
 NEUTROPHILS ARE ALSO IMPORTANT IN THE CHRONIC
DAMAGE INDUCED IN LUNGS BY SMOKING AND OTHER
IRRITANT STIMULI.
• IN ADDITION TO CELLULAR INFLTRATES, GROWTH
OF BLOOD VESSELS AND LYMPHATIC VESSELS IS
OFTEN PROMINENT IN CHRONIC INFLAMMATORY
REACTIONS.

• THIS GROWTH OF VESSELS IS STIMULATED BY

GROWTH FACTORS, SUCH AS VEGF, PRODUCED BY
MACROPHAGES AND ENDOTHELIAL CELLS
 GRANULOMATOUS
INFLAMMATION
• A DISTINCTIVE PATTERN OF CHRONIC INFLAMMATION.

• A LIMITED NUMBER OF INFECTIOUS AND SOME

NONINFECTIOUS CONDITIONS.

• A GRANULOMA IS A CELLULAR ATTEMPT TO CONTAIN AN

OFFENDING AGENT THAT IS DIFFICULT TO ERADICATE.

• THERE IS OFTEN STRONG ACTIVATION OF T LYMPHOCYTES

LEADING TO MACROPHAGE ACTIVATION, WHICH CAN CAUSE
INJURY TO NORMAL TISSUES.
 GRANULOMATOUS INFLAMMATION
• TUBERCULOSIS , SARCOIDOSIS, CAT-SCRATCH DISEASE,
LYMPHOGRANULOMA INGUINALE, LEPROSY, BRUCELLOSIS, SYPHILIS,
SOME MYCOTIC INFECTIONS, BERYLLIOSIS, REACTIONS OF IRRITANT
LIPIDS, AND SOME AUTOIMMUNE DISEASES
• A GRANULOMA IS A
FOCUS OF CHRONIC
INFLAMMATION lymphocytes

CONSISTING OF A
MICROSCOPIC
AGGREGATION OF
Macrophage
MACROPHAGES THAT s
ARE TRANSFORMED Plasma cells
(transforme Plasma cells
d into
INTO EPITHELIUM-LIKE epithelium
like cells)
CELLS, SURROUNDED BY
A COLLAR OF
MONONUCLEAR
LEUKOCYTES, lymphocytes

PRINCIPALLY
LYMPHOCYTES AND
• IN THE USUAL HEMATOXYLIN AND EOSIN–
STAINED TISSUE SECTIONS, THE EPITHELIOID
CELLS HAVE A PALE PINK GRANULAR CYTOPLASM
WITH INDISTINCT CELL BOUNDARIES, OFTEN
APPEARING TO MERGE INTO ONE ANOTHER.

• THE NUCLEUS IS LESS DENSE THAN THAT OF A

LYMPHOCYTE, IS OVAL OR ELONGATE, AND MAY
SHOW FOLDING OF THE NUCLEAR MEMBRANE.

• OLDER GRANULOMAS DEVELOP AN ENCLOSING

RIM OF FIBROBLASTS AND CONNECTIVE TISSUE.

• FREQUENTLY, EPITHELIOID CELLS FUSE TO

FORM GIANT CELLS IN THE PERIPHERY OR
SOMETIMES IN THE CENTER OF GRANULOMAS.
-Typical tuberculous granuloma showing
an area of central necrosis surrounded
THESE GIANT CELLS MAY ATTAIN DIAMETERS OF
by multiple Langhans-type giant cells,
40 TO 50 ΜM. THEY HAVE A LARGE MASS OF
epithelioid cells, and lymphocytes.
CYTOPLASM CONTAINING 20 OR MORE SMALL
NUCLEI ARRANGED EITHER PERIPHERALLY
(LANGHANS-TYPE GIANT CELL) OR
HAPHAZARDLY (FOREIGN BODY–TYPE GIANT
:THERE ARE TWO TYPES OF GRANULOMAS, WHICH DIFFER IN THEIR PATHOGENESIS
Foreign body
granulomas
Around meterials that are large
enough to preclude phagocytosis
by a single macrophage and do
not incite any specific
inflammatory or immune
response.(e.g.talc, sutures)
Epithelioid cells and giant
cells are apposed to the
surface of the foreign
body
Immune granulomas
A variety of agents that
are capable of inducing a
cell mediated immune
response (the inciting
agent is poorly
degradable)
Macrophages present
peptides to antigen-specific T
lymphocytes, causing their
activation.T cells produce
cytokines, such as IL-2,
which activates other T cells,
and IFN-γ, which is
important in activating
macrophages and
transforming them into
epithelioid cells and
multinucleate giant cells.
 • elevation of body • plasma proteins,
temperature (by 1 mostly synthesize in
to 4 c) the liver. • In bacterial

fibrinogen, and serum amyloid A SAA)

amyloid A (SAA) protein)
Acute-phase proteins (C-reactive protein (CRP),

Leukocytosis
• Produced in
fever

• plasma infections
response to concentrations may • The leukocyte count
substances called increase several
pyrogens usually climbs to
hundred-fold as 15,000 or 20,000
• Pyrogens stimulate part of the response cells/μL.
prostaglandin to inflammatory • it may reach
synthesis in the stimuli.
vascular and extraordinarily
• Synthesis of these high levels of 40,000
perivascular cells of molecules by
the hypothalamus. to 100,000 cells/μL.
hepatocytes is up- These extreme
• PGE2, stimulate the regulated by elevations are
production of cytokines. referred to as
neurotransmitters • bind to microbial leukemoid reaction.
such as cyclic cell walls, and act as • accelerated release
adenosine opsonins to fix
monophosphate, of cells from the
complement. bone marrow
which function to • bind chromatin,
reset the postmitotic reserve
temperature set aiding in the pool (caused by
point at a higher clearing of necrotic cytokines.
level. cell nuclei. • associated with a
• fever may induce rise in the number
heat shock proteins of more immature
that enhance neutrophils in the
lymphocyte blood.
 OTHER MANIFESTATIONS OF THE
ACUTE-PHASE RESPONSE
• INCREASED PULSE AND BLOOD PRESSURE.

• DECREASED SWEATING, MAINLY BECAUSE OF REDIRECTION OF

BLOOD FLOW FROM CUTANEOUS TO DEEP VASCULAR BEDS, TO
MINIMIZE HEAT LOSS THROUGH THE SKIN; RIGORS (SHIVERING),
CHILLS (SEARCH FOR WARMTH).

• ANOREXIA, SOMNOLENCE, AND MALAISE, PROBABLY BECAUSE

OF THE ACTIONS OF CYTOKINES ON BRAIN CELLS.
 SEVERE BACTERIAL INFECTIONS
(SEPSIS)
• LARGE AMOUNTS OF ORGANISMS AND LPS IN THE BLOOD
STIMULATE THE PRODUCTION OF ENORMOUS QUANTITIES OF
SEVERAL CYTOKINES, NOTABLY TNF AND IL-1.

• HIGH LEVELS OF CYTOKINES CAUSE VARIOUS CLINICAL

MANIFESTATION SUCH AS DISSEMINATED INTRAVASCULAR
COAGULATION, CARDIOVASCULAR FAILURE, AND METABOLIC
DISTURBANCE, WHICH ARE DESCRIBED AS SEPTIC SHOCK.
 CONSEQUENCES OF DEFECTIVE OR EXCESSIVE
INFLAMMATION

• increased susceptibility to infections.

• delayed wound healing, because
Defective inflammation is essential for clearing
inflammation damaged tissues and debris and provides
the necessary stimulus to get the repair
process started.

• Allergiesunregulated immune responses against

commonly encountered environmental antigens.
Excessive • autoimmune diseasesimmune responses develop
inflammatio against normally tolerated selfantigens.
• Prolonged inflammation and the fibrosis that
n accompanies it are also responsible for much of the
pathology in many infectious, metabolic, and other
diseases.
•THANK YOU 